Technical Field
The present invention generally relates to gene therapy vectors. In particular, the present invention relates to lentiviral vectors that provide gene therapy for adrenoleukodystrophy and adrenomyeloneuropathy.
Description of the Related Art
Childhood cerebral adrenoleukodystrophy (CCALD) is a very rare, sometimes rapidly progressive, x-linked genetic neurologic disorder in boys (median age of onset age 7; range 3-15 years) that, untreated, leads to a vegetative state, and ultimately death, within a median of 5 years after diagnosis.
CCALD often initially presents as Addison's disease, but the diagnosis is usually made based on “sudden” decreases in attention, thinking, concentration, and other cerebral functions with confirmatory findings of cerebral demyelination on magnetic resonance imaging (MRI). Prior to demyelination, the MRI of the patient's brain is normal, and there are no neurodevelopmental abnormalities. The clinical course may be “slow” at first, but can become rapidly progressive and irreversible with the widespread loss of myelin in the brain. The terms “slow” and “sudden” are relative in that the duration of demyelination is not truly known, but the rapid decrease in cognitive and motor function can happen at any time and for unknown reasons. Indeed, the MRI changes precede symptoms, and can be floridly abnormal with widespread demyelination at a time when there are very few clinical manifestations of the disease. The incidence of x-linked adrenoleukodystrophy (ALD) in the United States is about 1:21,000 male births with about 35% developing CCALD; about 35 to 40 boys are diagnosed with CCALD each year. The cause of the disease is a mutation of the ATP-binding cassette, sub-family D (ALD), member 1 (ABCD1) gene leading to a dysfunctional or absent adrenoleukodystrophy protein (ALDP) gene product. ALDP localizes to cellular peroxisomes, where it participates in the degradation of very long chain fatty acids (VLCFA) (chain lengths of >20 carbons) to shorter fatty acids, which are used to maintain cellular structure and function.
The pathophysiology of the central nervous system (CNS) manifestations of CCALD is not well understood, but demyelination arises due to a local accumulation of VLCFA that cannot be metabolized because the defective ALDP does not support that process in the brain microglia. The rapidly progressive phase of the disease is caused by inflammation, possibly caused by acylation of cellular proteins by the VLCFA, which increases the loss of myelin. The rapidly progressive phase of CCALD can result in a boy deteriorating from normal function to severely disabled within months.
The only available treatment is allogeneic hematopoietic stem cell transplant (HCT) to supply cells that produce functional ALDP. Since the brain microglia are derived from the bone marrow, fully matched related donor human stem cell transplantation using cells producing functional ALDP can potentially ameliorate or stop the progression of demyelination. However, because it takes 12 to 18 months for allogeneic HCT to stabilize the disease, and because of the progressive nature of the disease, transplantation should be done as soon as possible upon diagnosis. This is sometimes problematic because of the lead times needed to find related or unrelated matched bone marrow stem cell donors. The use of allogeneic stem cells also presents a risk of graft failure and the development of acute and chronic graft versus host disease (GvHD). These complications can lead to death and are increased in incidence when unrelated donors are utilized as a source for allogeneic hematopoietic stem cells.
Another source of ALDP replacement is the use of matched are, more typically, partially matched cord blood cell transplants. The use of cord blood stem cells (CBSCs) is problematic, with a risk of graft failure and prolonged time to engraftment requiring extended transfusion support. Indeed, all forms of allogeneic HCT involve a 10-15% risk of transplant related mortality, and up to a 30% risk of chronic graft versus host disease.
Thus, there is a need in the art for safer and more efficient adrenoleukodystrophy therapies. The present invention provides solutions to these and other problems.